Cancer is still a life-threatening disease affecting an increasing number of people in the world. Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic compounds used for treating cancer. However, a significant number of patients have acquired or develop resistance to these chemotherapeutic compounds after initial therapeutic treatments. Such drug-resistance in cancer is the major impediment to a successful treatment. Such cells display a reduced sensitivity to chemotherapeutic compounds based on several mechanisms in particular including an increase in drug efflux such as by an increased expression or activity of ABC transporter proteins such as P-glycoprotein (P-gp, MDR1, or ABCB1) or affected apoptosis pathways such as by mutated or dysfunctionally regulated genes and respective proteins. For example, cancer cells lacking cell death mediators Bax and Bak have been reported to develop drug-resistance and the high frequency of p53 mutations is expected to lead to a drug resistance of cancer cells, too.
Studies also revealed that ABC transporter protein, in particular P-glycoprotein, acts as a major barrier to drug treatment in various diseases due to its high expression in cells and/or tissues. In addition to cancer, the diseases showing ABC-protein-dependent drug resistance include fungal infections, bacterial infections, AIDS, CNS diseases such as Alzheimer's disease and epilepsy, congestive heart failure, etc. It is believed that the alternation of functional activity of P-glycoprotein in a subject is a way to improve and/or optimize therapeutic efficacy of a treatment in said subject.
Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms and targets for treating cancer which are also suitable to overcome drug resistance. It is also believed that a therapeutic agent being effective in inhibiting the expression of ABC transporter proteins such as P-glycoprotein may also be suitable in treating a subject suffering a disorder associated with an altered expression or overexpression of the ABC transporter protein.
Transition metal ions are essential for the proper functions of organisms; examples including copper, iron, and manganese ions work with proteins and enzymes for multiple biological processes such as electron transfer and catalysis. As metals are involved in redox activity, coordination, and reactivity towards organic substrates in organisms, and are tightly regulated under normal conditions, aberrant metal ion concentrations are associated with pathogenesis of diseases, in particular of cancers. For instance, enriched copper ions found in cancer tissues are suggested to promote the angiogenesis processes in tumors.
In fact, metal-containing compounds have been used to treat a wide range of diseases. For example, cisplatin (cis-[PtII(NH3)2Cl2]) can bind to the purine bases of the DNA, thereby led to DNA damage resulting in apoptosis in cancer cells. However, due to severe side effects such as dose-dependent toxicity, allergy, effects on the kidneys and immunity, gastrointestinal disorders, hemorrhage and loss of hearing, the clinical use of cisplatin is limited. Acquired resistance to cisplatin is caused by an increased efflux or detoxification of the drug, increased rate of DNA repair, as well as a reduced susceptibility of cancer cells in response to drug-induced cell death. Other platinum-containing anti-cancer analogs such as carboplatin and oxaliplatin are therefore used as alternative to cisplatin and further transition metal complexes including zinc(II), copper(II), gold(III), copper chelating agents, and non-platinum metal complexes such as ruthenium-containing compounds were studied for their potential as anti-cancer agents, too.
The exploration and exploitation of other non-platinum anti-cancer drugs have received considerable attention. In view of the fact that soluble cobalt salts can adversely interfere with cell division and bind to nucleic acids inside the cell nucleus, one may postulate that cobalt complexes could work as anti-cancer agents like platinum-containing analogs. However, they were also reported for being weakly mutagenic and inducing metastasis in animal models (Jensen A. A. and Tuchsen F., Crit Rev Toxicol, 1990, 20, 427-437). There have been some examples of cobalt(III) complexes with equatorial tetradentate Schiff base ligands as potent inhibitors of a wide range of zinc-dependent proteins (Heffern, M. C. et al., Curr Opin Chem Biol, 2013, 17, 189-196, Takeuchi, T. et al., J. Am. Chem. Soc., 1998, 120, 8555-8556, Harney, A. S. et al., Proc Natl Acad Sci USA, 2009, 106, 13667-13672, Peterson, M. D, J Am Chem Soc, 2013, 135, 13162-13167), however, the related use of cobalt pyridine complexes in biological applications or specifically for the development of anti-cancer drugs remains substantially unexplored (Luis, D. V. et al., J Biol Inorg Chem, 2014, 19, 787-803, Vignesh, G. et al., Rsc Advances, 2014, 4, 57483-57492). On the other hand, cobalt(II)/(III) complexes with pyridine ligands have recently been developed as redox mediators in dye-sensitized solar cells (DSCs) (Feldt, S. M., et al., J Am Chem Soc, 2010, 132, 16714-16724, Klahr, B. M. and Hamann, T. W., J Phys Chem C, 2009, 113, 14040-14045, Xie, Y. and Hamann, T. W., J Phys Chem Lett, 2013, 4, 328-332, Kim, H. S. et al., Chem Commun (Camb), 2011, 47, 12637-12639, Sun, Z. et al., Acc Chem Res, 2015, 48, 1541-1550), but not in the field of cancer treatment or the specific treatment of multidrug-resistant cancer.
Although there has been increased research in this regard, there remains a strong need for methods and means allowing for an effective therapeutic treatment of cancer, especially of multidrug-resistant cancer and cancer cells with a multidrug-resistant phenotype, respectively. Also, efficacious treatment options are urgently required for specifically treating subjects with a disorder associated with an overexpression of ABC transporter proteins.